IC14 Pharmaco III (PD, AD)

Question 1

PD definition

Answer 1

neurodegenerative disease where nerve cell lose function over time and die, progressive, incurable, increases with age

Question 2

degeneration of basal ganglion neurons causes

Answer 2

decrease dopamine -> PD

Question 3

degeneration of neuro cortex

Answer 3

decrease acetylcholine -> AD

Question 4

epidemiology of PD

Answer 4

• incidence increases with age
• avg onset: 60s
• young onset PD: 21-40yo
• juvenile onset PD: <20

Question 5

motor sx of PD

Answer 5

TRAP (TRA - cardinal features of PD)
- tremor at rest
- rigidity (cogwheel)
- akinesia/ bradykinesia (slow movement)
- postural instability/ gait disturbances

Question 6

pathophysiology of PD

Answer 6

1. aggregation of misfolded alpha-synuclein -> form Lewy body
2. failure to clear Lewy body (contains alpha-synuclein and ubiquitin)

• Effect: degeneration of dopaminergic neurons with Lewy body inclusion in the substantia nigra -> dysfunction of the nigrostriatal pathway

Question 7

diagnostic test to confirm PD

Answer 7

Lewy body eosinophilic cytoplasmic inclusions in basal ganglia

Question 8

function of substantia nigra

Answer 8

involved in action selection
- basal ganglia normally inhibit a number of motor sx
- substantia nigra mediated release of inhibition -> allows action to occurs

Question 9

what happen when there is a loss of substantia nigra?

Answer 9

no release of inhibition -> hypokinetic state (decreased in motor movements)

Question 10

how is dopamine synthesised endogenously?

Answer 10

• L-tyrosine -> L-DOPA (tyrosine hydroxylase)
• L-DOPA -> dopamine (DOPA carboxylase)

Question 11

Dopamine and L-DOPA which one can pass BBB?

Answer 11

Dopamine - cannot pass BBB
L-DOPA - can pass BBB

Question 12

Drug of choice for PD

Answer 12

levodopa (synthetic L-DOPA) + DCI (carbidopa/ benserazide)

Question 13

Function of DCI

Answer 13

peripherally DOPA carboxylase inhibitor -> prevent systemic SE due to excessive dopamine

Question 14

SE of levodopa

Answer 14

short term: N/V/ postural hypotension
long term: motor functions, dyskinesia (does not go away after discontinuation)

Question 15

eg of COMT inhibitors and MOA

Answer 15

entacapone, tolcapone
- MOA: block COMT from breaking down dopamine/ L-DOPA to inactive form -> more levodopa enter brain

Question 16

can COMT be used as monotx

Answer 16

no, must be taken with levodopa

Question 17

SE of COMT

Answer 17

dyskinesia, nausea, diarrhoea, urinary discolouration, visual hallucinations, daytime drowsiness, sleep disturbances
- tolcapone: liver dysfunction

Question 18

MAO-Bi eg

Answer 18

seligiline, rasagiline
- inhibit MAO-B that breakdown dopamine

Question 19

can MAO-Bi be used as a monotx

Answer 19

yes for mild PD

Question 20

SE of MAO-Bi

Answer 20

heart-burn, loss of appetite, anxiety, palpitation, insomnia, nightmares, visual hallucinations (too much dopamine)

Question 21

dopamine agonist eg and MOA

Answer 21

ropinirole, pergolide, pramipexole, rotigotine (patch), apomorphine (SC)
- MOA: act directly on dopamine receptors to reduce sx of PD

Question 22

why is dopamine agonist preferred over levodopa for young onset PD?

Answer 22

prevent or delay motor complications with levodopa (eg dyskinesia)

Question 23

SE of dopamine agonsit

Answer 23

common: N/V/OH, headache, dizziness, cardiac arrhythmia

• pergolide ‘ergot’ derivative: peritoneal fibrosis, cardiac valve regurgitation

pramipexole, ropinirole: sedation, somnolence, daytime sleepiness

Question 24

non-dopamine pharmacological approach for PD

Answer 24

amantadine and anticholinergics (trihexyphenidyl/benzhexol)

Question 25

MOA of amantadine

Answer 25

- release stored dopamine - inhibit presynaptic uptake of catecholamine - dopamine agonist - NMDA receptor antagonist

Question 26

amantadine place in tx for PD

Answer 26

- monotx or adjunct to levodopa - can reduce dyskinesia

Question 27

SE of amantadine

Answer 27

cognitive impairment (inability to concentrate), hallucination, insomnia, nightmares, livedo reticularis (venule swelling due to thrombosis)

Question 28

advantages of anticholinergics

Answer 28

- can control tremor, treat sialorrhoea/ drooling - used as an adjunct to levodopa to treat tremors in PD

Question 29

SE of anticholinergics

Answer 29

dry mouth, sedation, constipation, urinary retention, confusion, hallucinations

Question 30

dementia vs delirium

Answer 30

dementia- occurs for at least 6mths delirium <6mths

Question 31

sx of dementia

Answer 31

cognition impairment (at least 2): - memory - language - attention - problem solving

Question 32

Pathophysiology of AD

Answer 32

aggregation of abnormal proteins 1. senile plaques (aggregates of beta-amyloid peptides) 2. neurofibrillary tangles (aggregates of hyperphosphorylated tau proteins) 3. brain atrophy to aggregation at neuro cortex (shrinking of hippocampus) 4. neurodegeneration of neurons at cortex affecting multiple NT (acetylcholine, 5HT, glutamate)

Question 33

what are the neurotransmitters affected in AD. which NT causes clinical features of AD?

Answer 33

acetylcholine 5HT glutamate - cholinergic deficits causes clinical features of AD

Question 34

difference btw monoaminergic and cholinergic synapse

Answer 34

breakdown of acetylcholine occurs in synapse but breakdown of dopamine and 5HT occurs in presynaptic neurons after reuptake

Question 35

goals of tx for AD

Answer 35

delay need to institutionalise, improve QOL for both patients and caregivers

Question 36

pharmacological tx for AD

Answer 36

AChEI, NMDA receptor antagonist

Question 37

Eg of AChEI and MOA

Answer 37

donepezil (best), rivastigmine, galatamine - MOA: inhibit AChE -> increase ACh in synapse

Question 38

rivastigmine vs galatamine (tested)

Answer 38

- rivastigime: PO, patch, shorter half life, metabolised by kidneys - galatamine: PO, longer half life, also act on nicotinic receptors, metabolised by liver

Question 39

SE of AChEI (tested)

Answer 39

Cholinergic hyper-activation: N/V/D less common: (parasympathetic -> rest and digest) muscle cramp, bradycardia, loss of appetite, increase gastric acid secretion

Question 40

which AChEI can be used for moderate AD?

Answer 40

donepezil, rivastigmine, galantamine

Question 41

which AChEI can be used for severe AD?

Answer 41

donepezil

Question 42

memantine MOA, indication

Answer 42

non competitive NMDA receptors antagonist -> block excitotoxicity - for moderate to severe AD

Question 43

mx of BPSD

Answer 43

prescribe the lowest dose possible to alleviate sx and adjust dosage as necessary